BR112015016917B1 - ORAL DOSAGE FORM OF GASTRIC RETENTION, AND, USE OF A BILIARY ACID SEQUESTRANT - Google Patents

Abstract

ORAL DOSAGE FORM OF GASTRIC RETENTION, AND, USE OF A BILIARY ACID SEQUESTRANT. Novel methods and compositions are described herein for controlling the release of bile acid sequestrant to the stomach in order to treat or prevent upper GI tract disorders or throat disorders. The methods generally include administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one bile acid sequestrant dispersed in a polymeric matrix. The bile acid sequestrant composition can be administered alone or in combination with the proton pump inhibitor, and, optionally, at least one or more agents selected from antacids, histamine H2 receptor antagonists, (Beta)-agonists, (Gamma)-aminobutyric acid (GABA-B), GABA-B agonist prodrugs, acid pump antagonists, protease inhibitors and GC-C agonists.

Description

CROSS REFERENCE TO RELATED ORDERS

[0001] This application is a U.S. National Phase deposit. under 35 U.S.C. § 371 of International Application PCT/US2014/011450, filed January 14, 2014, and published as WO 2014/113377 on July 24, 2014. PCT/US2014/011450 claims priority of the United States provisional patent application 61 /752,726, filed January 15, 2013 and United States Provisional Patent Application 61/914.04, filed December 11, 2013, the disclosures of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present disclosure generally relates to gastric retention sustained release oral dosage forms comprising a bile acid sequestrant. It also relates to methods of treating upper gastrointestinal tract and throat disorders by administering said dosage forms.

FUNDAMENTALS OF THE INVENTION

[0003] Anatomically, the upper gastrointestinal tract consists of the mouth, a portion of the throat, the esophagus, the stomach, and the duodenum, the uppermost part of the small intestine.

[0004] The esophagus transports food, fluid and saliva from the mouth to the stomach by coordinated contractions of its muscular lining. This process is automatic and people are usually not aware of it. Many people feel their esophagus when they swallow something too big, try to eat too quickly, or drink liquids that are too hot or too cold. They then feel the movement of food or drink down the sphincters. When a person swallows, the sphincters automatically relax and allow food or drink to pass from the mouth into the stomach. The muscles then close quickly to prevent swallowed food or drink from leaking from the stomach back into the esophagus or mouth. These sphincters make it possible to swallow while lying down or even upside down. When people burp to release swallowed air or gas from carbonated drinks, the sphincters relax and small amounts of food or drink quickly return; this condition is called reflux. The esophagus quickly squeezes the material back into the stomach. This amount of reflux and the reaction to it by the esophagus is considered normal.

[006] Although many people are familiar with acid reflux, the influx of caustic acids from the stomach into the esophagus, bile reflux is less well known. Bile reflux occurs when bile, a digestive fluid produced in the liver, flows up (reflows) from the small intestine into the stomach and then into the esophagus. Bile reflux often accompanies acid reflux, and together they can cause inflammation of the lining of the esophagus and potentially increased risk of esophageal cancer. See AJG (1999) 94(12):3649-3650. Bile reflux can also affect the stomach, where it can cause additional inflammation in the stomach (gastritis which, if left untreated, can lead to peptic ulcers).

[007] Unlike acid reflux, bile reflux typically cannot be controlled by dietary or lifestyle changes. In contrast, bile reflux is most often managed with certain medications or, in severe cases, with surgery. No solution is uniformly effective, however, and some people continue to have bile reflux even after treatment.

[008] Bile acids are steroid acids found predominantly in the bile of mammals. They are produced in the liver by oxidation of cholesterol and are stored in the gallbladder and secreted into the intestine in the form of salts. They act as surfactants, emulsifying lipids and aiding in the absorption and digestion of dietary fat and cholesterol.

[009] The main bile acids are: cholic acid, chenodeoxycholic acid, deoxycholic acid, taurocholic acid and glycocholic acid. The chemical distinctions between different bile acids are small, depending solely on the presence or absence of hydroxyl groups at positions 3, 7 and 12. In humans, the most prevalent bile acids are cholic acid and chenodeoxycholic acid and their conjugates with taurine and glycine (glycocholate and taurocholate). Some mammals predominantly synthesize deoxycholic acid.

[0010] Bile acid synthesis is a major consumer of cholesterol. The body synthesizes about 800 mg of cholesterol a day and about half of which is used for bile acid synthesis. In total, about 20-30 grams of bile acids are secreted into the intestine daily; about 90% of the bile acids excreted are reabsorbed (by active transport in the ileum) and recycled. This is referred to as enteropathic circulation. Since bile acids are made from endogenous cholesterol, enteropathic circulation of bile acids can be disrupted as a way of lowering cholesterol. This is usual therapeutic reasoning for administration of bile acid sequestrants.

[0011] Bile reflux can be difficult to distinguish from acid reflux because the signs and symptoms are similar and the two conditions often occur at the same time. Unlike acid reflux, bile reflux inflames the stomach, often causing a burning or burning pain in the upper abdomen. Other signs and symptoms may include: frequent heartburn, ie a burning sensation in the chest that sometimes spreads to the throat along with a bitter taste in the mouth; nausea; bile vomiting; a cough; or hoarseness.

[0012] Bile and stomach acid reflux into the esophagus when the lower esophageal sphincter (LES) malfunctions. The LES separates the esophagus and stomach. Normally, it opens only to allow food to pass through the stomach and then closes tightly. But if the valve abnormally relaxes or weakens, stomach acid and bile can wash back into the esophagus, causing heartburn and constant inflammation that can lead to serious complications.

[0013] A sticky mucous coating protects the stomach from the corrosive effects of stomach acid, but the esophagus lacks this protection, which is why bile reflux and acid reflux can seriously damage esophageal tissue. And while bile reflux can damage the esophagus on its own — even when the reflux pH is neutral or alkaline — the combination of bile and acid reflux appears to be particularly harmful, increasing the risk of complications.

[0014] Anatomically, the throat consists of the trachea, the pharynx and the larynx. The throat is separated from the esophagus by the epiglottis, a flap that separates the esophagus from the windpipe (the windpipe) and prevents the inhalation of food or drink into the lungs. The pharynx, situated immediately inferior (below) the mouth and nasal cavity and superior to the esophagus and larynx is considered part of the digestive system as well as the respiratory system. The larynx, commonly called the voice box, is involved in breathing, producing sound, and protecting the trachea from aspiration of food. It manipulates the slope and volume. The larynx houses the vocal folds (commonly called the “vocal cords”), which are essential for phonation. The vocal folds are situated just below where the pharyngeal tract separates into the trachea and esophagus. Due to the anatomical proximity of the upper GI tract and the throat and the fact that both systems are separated only by the epiglottis, bile acid can sometimes reflux into the throat producing additional symptoms.

[0015] Disorders and/or symptoms believed to be associated with bile reflux, either alone or in combination with acid reflux, include, for example, heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, esophageal ulcers, esophagitis, laryngitis, pharyngitis, deep or hoarse voice, and GERD-related lung dysfunction, such as cough and/or asthma. Additional complications believed to occur as a result of chronic bile reflux are, for example, gastroesophageal reflux disease or GERD; Barrett's esophagus; esophageal cancer (eg, adenocarcinoma) and gastritis.

[0016] GERD is a generic term that encompasses diseases with various digestive symptoms, such as heartburn, acid regurgitation, obstructed admiration, aphagia, pectoralgia, permeation sensation and similar sensitivity caused by reflux in the esophagus and stagnation of gastric contents, duodenal juice , pancreatic juice and the like. The term covers both reflux esophagitis in which erosion and ulcers are observed endoscopically and non-ulcer esophageal regurgitation (NUD) dyspepsia in which no abnormalities are observed endoscopically. GERD occurs when the LES does not close properly and stomach contents leak back or reflux into the esophagus.

[0017] A hiatal hernia can contribute to causing GERD and can happen in people of any age. Other factors that can contribute to GERD include, but are not limited to, alcohol use, being overweight, pregnancy, smoking, Zollinger-Ellison syndrome, hypercalcemia, and scleroderma. Also, certain foods may be associated with reflux events, including, citrus fruits, chocolate, caffeinated beverages, fatty and fried foods, garlic and onions, mint flavor, spicy foods, and tomato-based foods such as spaghetti sauce, chili and pizza.

[0018] The inner mucosa of the esophagus is lined with non-keratinized stratified squamous epithelium arranged in longitudinal folds. Damage to the lining of the esophagus causes the normal squamous cells that line the esophagus to transform into a type of cell not normally found in humans, called specialized columnar cells. This conversion of cells in the esophagus by acid reflux is known as Barrett's esophagus. Although people who do not have heartburn can have Barrett's esophagus, it is observed to be about three to five times more common in people with this condition. Barrett's esophagus does not itself cause the symptoms and is important only because it appears to precede the development of a particular type of cancer—esophageal adenocarcinoma. The risk of developing adenocarcinoma is 30 to 125 times greater in people who have Barrett's esophagus than in people who don't. This type of cancer is rapidly growing in white men. This increase may be related to the increase in obesity and GERD.

[0019] Barrett's esophagus has no cure, cut surgical removal of the esophagus, which is a serious operation. Surgery is recommended only for people who have a high risk of developing cancer or who already have it. Most physicians have recommended treating GERD with acid-blocking drugs, as it is sometimes associated with improvement in Barrett's tissue extent. However, this approach has not been proven to reduce the risk of cancer. Treating reflux with a surgical procedure for GERD also doesn't seem to cure Barrett's esophagus. Several different experimental approaches are under study. An attempt to see if destruction of Barrett's tissue by heat or other means through an endoscope can eliminate the condition. This approach, however, has potential risks and unknown effectiveness.

[0020] Esophageal cancer can occur almost anywhere the size of the esophagus, but if it often starts in the glandular cells closest to the stomach (adenocarcinoma). Because esophageal cancer cannot be diagnosed until it is very advanced, the outlook for people with the disease is often poor. The risk of esophageal cancer is increased by long-term irritation of the esophagus, such as with smoking, heavy alcohol intake, and Barrett's esophagitis. So, there is a link between esophageal cancer and bile reflux and acid reflux. In animal models, bile reflux has been shown to cause only esophageal cancer.

[0021] There are numerous medications that treat heartburn and indigestion. Currently, the main therapies employed in the treatment of GERD and upper GI disorders include agents to reduce stomach acidity, for example using histamine H2 receptor antagonists or proton pump inhibitors (PPIs). H2 blockers are drugs that inhibit the production of acid in the stomach. Exemplary histamine receptor antagonists include, for example, cimetidine (sold under the tradename TAGAMET HB®), famotidine (sold under the tradename PEPCID AC®), nizatidine (sold under the tradename AXID AR®), and ranitidine (sold under the tradename AXID AR®). under the trade name ZANTAC 75®). Both types of medication are effective in treating heartburn caused by acid reflux and typically eliminates symptoms in a short period of time.

[0022] PPIs act by inhibiting the parietal cell proton H+/K+ ATPase pumps responsible for acid secretion from these cells. PPIs such as omeprazole and pharmaceutically acceptable salts thereof are described, for example, in EP 05129, EP 124495 and U.S. patent. At the. 4,255,431.

[0023] Despite their well-documented effectiveness, PPIs have notable limitations. For example, patients who are unresponsive to treatment with a PPI inhibitor alone may be unresponsive because even though PPI is decreasing stomach acid reflux, bile acid from the duodenum is still present. Thus, an improvement in PPI-mediated activity is a well-recognized challenge in gastroenterology, and there is a need in the art to address and overcome upper GI tract disorders, as well as related throat disorders as discussed earlier, that are unresponsive to treatment by PPI. administration of PPIs alone.

[0024] In this way, the development of an effective treatment for conditions in which bile reflux is involved, whether in conjunction with acid reflux or not, could be used.

SUMMARY

[0025] The present invention addresses this problem by providing an oral dosage form that is capable of long-term and stable delivery of a bile acid sequestrant to the stomach at concentrations that allow optimal binding of bile acids refluxed from the small intestine into the stomach, thus preventing damage. of bile acid to the stomach lining, as well as preventing backflow of bile acids from the stomach into the esophagus and other parts of the upper GI and throat, preventing further damage.

[0026] In one embodiment, a gastric retention oral dosage form for sustained release of a bile acid sequestrant to the stomach for the treatment of a disease of the upper gastrointestinal tract or throat is described. In this embodiment, the dosage form comprises a bile acid sequestrant dispersed in a polymeric matrix. The polymer matrix comprises one or more hydrophilic polymers such that, upon inhibition of gastric fluid, the dosage form swells to a size sufficient to promote gastric retention for a period of time of 3 hours or more. The bile acid sequestrant is released from the dosage form by eroding the polymer matrix for an extended period of time of at least 3 hours.

[0027] In one embodiment, a method for preparing the gastric retention oral dosage form described herein is described. This method comprises combining and mixing intragranular components to form an intragranular mixture. Then, the intragranular mixture is compressed into pieces. These pieces are then crushed to form crushed granulation. Extragranular components are combined and blended to form an extragranular mixture. The extragranular components and ground granulation are then combined and blended to form a dry blend. Extragranular components can be blended and blended at any time prior to blending with the crushed granulation.

[0028] In one embodiment, a method of administering a therapeutically effective amount of a daily dosage of from about 100 mg to about 4,000 mg of a bile acid sequestrant to a subject in need thereof is described. This method comprises administering to the subject the gastric retention oral dosage form described herein when the subject is in the fed state.

[0029] In one embodiment, a method of treating an individual suffering from a selected disease of heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, esophageal ulcers, esophagitis, laryngitis, pharyngitis, hoarse voice, disease of gastroesophageal reflux disease (GERD), Barrett's esophagus, gastric cancer, esophageal cancer, gastritis and GERD-related lung dysfunction. This method comprises administering to the subject a total daily dosage of from about 100 mg to about 4000 mg of a bile acid sequestrant in the form of the gastric retention oral dosage form described herein. In some embodiments, the esophageal cancer is adenocarcinoma.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 demonstrates drug release rates from various embodiments of the invention.

[0031] Figure 2 demonstrates the effect of coating level on the drug release rate of an embodiment of the invention.

[0032] Figure 3 demonstrates the effect of coating level on the drug release rate of an embodiment of the invention.

[0033] Figure 4 demonstrates the effect of coating level on the drug release rate of an embodiment of the invention.

[0034] Figure 5 demonstrates the effect of coating level on the drug release rate of an embodiment of the invention.

[0035] Figure 6 demonstrates the effect of coating level on the drug release rate of an embodiment of the invention.

[0036] Figure 7 shows in vitro drug release and disintegration times for embodiments of the invention subsequently used in dogs.

[0037] Figure 8 demonstrates in vitro erosion times of various formulations of the invention in dogs.

[0038] Figure 9 demonstrates the swelling ability of tablets of various embodiments of the invention.

DETAILED DESCRIPTION

[0039] Reference will now be made to certain embodiments of the invention, examples of which are illustrated in the attached structures, formulas and figures. While the invention is described in conjunction with the numbered embodiments, it is understood that they should not limit the invention to the embodiments. Rather, the invention shall cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein, but includes any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ or contradict this patent application including, but not limited to, defined terms, term usage, described techniques or the like, this patent application governs.

[0040] As previously employed and throughout the description, the following terms are provided to assist the reader. Unless otherwise defined, all art terms, notations and other scientific or medical terms or terminology used herein shall have the meanings commonly understood by those skilled in the chemical, pharmaceutical and medical art. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for reading reference and the inclusion of such definitions here should not necessarily be considered to represent a substantial difference over the definition of the term as generally understood in the art. unless otherwise indicated.

[0041] The terms “drug”, “agent”, “active pharmaceutical ingredient (API)”, “active”, “active ingredient (AI)” or “mass active” are used interchangeably throughout this description to refer to the substance in a “pharmaceutical product” (i.e., a “drug” or “medication” or “drug product”) that is biologically active. Some medications may contain more than one active ingredient.

[0042] As used herein, a "formulation" or "pharmaceutical composition" comprises the API and one or more pharmaceutically acceptable excipients.

[0043] The term "dosage form" or "unit dosage form" as used herein refers to a structure, such as a capsule, pill, tablet, emulsion or syrup, prepared in accordance with a specific procedure of a pharmaceutical formulation or composition that delivers a "dose" or measured amount of API to the patient. Dosage forms provide an easily controllable dosage of the drug and enable patient adherence to the prescribed regimen. Several dosage forms may exist for the same compound, as different medical conditions may warrant different routes of administration.

[0044] In some embodiments, the dosage form described herein is an oral solid dosage form. In other embodiments, said solid oral dosage form is a tablet. In some embodiments, the dosage form may be administered multiple times within a 24 hour period in order to achieve a desired pharmacological effect.

[0045] The terms "gastric fluid" and "gastric juice" are used interchangeably throughout the description and refer to the endogenous fluid medium of the stomach, including water and secretions. “Simulated gastric fluid” means any fluid that is generally recognized as providing a substituent used for authentic gastric fluid in in vitro experiments designed to estimate the chemical or biological behavior of substances in the stomach. A simulated gastric fluid like this is aqueous 0.1 N HCl, pH 1.2. It is understood that the term "gastric fluid" or "gastric juice" used throughout the description and claims encompasses both authentic (ie, endogenous) gastric fluids and simulated gastric fluids.

[0046] The term "gastric retention dosage form" denotes dosage forms that effect prolonged release of the active ingredient compared to conventional dosage forms, such as customary tablets or capsules, while avoiding an undesirably high initial dose, the release being effected continuously over a relatively long and prolonged period at a therapeutically effective level by prolonged retention of the dosage form in the stomach.

[0047] "Controlled drug delivery systems" deliver the drug to the body in a precisely controlled manner to suit the drug and conditions being treated. The primary claim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time. The term "controlled release" is often used to refer to a variety of methods that modify the release of a drug from a dosage form. This term includes preparations marked "extended release", "delayed release", "modified release" or "extended release". In general, controlled release of the agents described herein can be provided by the use of a wide variety of polymeric carriers and controlled release systems including edible and inedible matrices.

[0048] “Extended release” or “extended release” preparations are the most common applications of controlled release and throughout this description both terms will be used interchangeably.

[0049] A drug "release rate" as used herein refers to the amount of drug released from a dosage form or pharmaceutical composition per unit of time (mg/hr). Drug release rates for drug dosage forms are typically measured as an in vitro dissolution rate, i.e., an amount of drug released from the dosage form or pharmaceutical composition per unit time measured under appropriate conditions in a suitable fluid. Tests can be performed, for example, at about pH 1.2 (modified simulated gastric fluid or mSGF) or at about pH 4.5 (the average pH of the stomach after a meal, simulating the fed state). Such a test can also be carried out, for example, at 37°C or 25°C. Suitable aliquots of the release rate solution (or suspension) are tested to determine the amount of drug released from the dosage form or pharmaceutical composition. A number of analytical techniques, eg HPLC, can be used to quantify the amount of drug released.

[0050] As used herein, a "therapeutically or pharmaceutically effective amount" of a drug or agent is an amount of a drug or agent (e.g., a bile acid sequestrant) that, when administered to a subject with a disease or condition, will have the intended therapeutic effect, for example, alleviating, ameliorating, alleviating or eliminating one or more manifestations of the disease or condition in the individual. The full therapeutic effect does not necessarily occur upon administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The term "therapeutically effective amount" as used herein also means that amount of active compound or pharmaceutical agent that elicits the biological medicinal response in a tissue, system, animal or human that is sought after by a researcher, veterinarian, physician or others. The therapeutically or pharmaceutically effective amount of the compound to be administered will be governed by such considerations and is the minimum amount necessary to alleviate, cure or treat the disease or disorder or one or more of its symptoms.

[0051] As used herein, a "prophylactically effective amount" of a drug or agent is an amount of a drug or agent (e.g., a bile acid sequestrant) that, when administered to a subject, will have the intended prophylactic effect. , for example, preventing or delaying the onset of action (or recurrence) of disease or symptoms or reducing the likelihood of onset of action (or recurrence) of disease or symptoms. The full prophylactic effect does not necessarily occur upon administration of one dose and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The term "prophylactically effective amount" also refers to an amount effective in preventing or substantially decreasing the chances of acquiring a disease or disorder or in reducing the severity of the disease or disorder before it is acquired or in reducing the severity of one or more of their symptoms before symptoms develop. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease or symptom) and secondary prophylaxis (as long as the disease or symptom has already developed and the patient is protected against the worsening of this process).

[0052] As used herein and as may be understood by one skilled in the art, citation of "a compound" shall include any solid forms of such compound, including the amorphous form, polymorphs and salts of the compound or a mixture of any forms such as these of the compound in any ratio, as may be applicable.

[0053] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.

[0054] When the compounds are basic, salts can be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present disclosure include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic acid , methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present disclosure include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. For use in medicine, the salts will be pharmaceutically acceptable salts. Other salts, however, can be used in the preparation of the compounds of the disclosure or pharmaceutically acceptable salts thereof. When the compound is basic or contains a sufficiently basic bioisostere, salts can be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenic salts , bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and palmoate (i.e. 1,1'-methylene-bis-( 2-hydroxy-3-naphthoate)).

[0055] In some embodiments, the salts may be prepared in situ during the isolation and final purification of the compounds. In other embodiments the salts can be prepared from the free form of the compound in a separate synthetic step.

[0056] When the compound is acidic or contains a sufficiently acidic bioisostere, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc salts and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N1- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0057] The preparation of the pharmaceutically acceptable salts described herein and other typical pharmaceutically acceptable salts is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, which is incorporated herein by reference.

[0058] Bile acid sequestrants are drugs that bind to bile acids in the small intestine and remove them from the body. This causes the body to use more cholesterol to make more bile acids, which are secreted into the small intestine, bound to bile acid sequestrants and carried out of the body. The end result is lower cholesterol level. Bile acid sequestrants also prevent the absorption of some dietary cholesterol.

[0059] Bile acid sequestrants currently approved for human use are polymeric compounds that serve as ion exchange resins. Bile acid scavengers exchange anions such as chloride ions for bile acids. In doing so, they bind to bile acids and sequester them from the enterohepatic circulation. Since bile acid sequestrants are large polymeric structures, they are not absorbed from the intestine into the bloodstream. Thus, bile acid sequestrants, along with any drug-bound bile acids, are excreted via the feces after passage through the gastrointestinal tract. Exemplary bile acid sequestrants include, for example, cholestyramine (sold under the tradename QUESTRAN®), colesevelam (sold under the tradename WELCHOL®), Selevamer (Rinogel®), and colestipol (sold under the tradename COLESTID®) and salts pharmaceutically acceptable thereof.

[0060] Oral gastric retention dosage forms make use of one or more hydrophilic polymers that swell upon ingestion of water from gastric fluid. When administered in the fed mode, when the diameter of the pyloric sphincter is contracted and reduced, these dosage forms will swell to a size that is too large to pass through the pyloric sphincter and are retained in the stomach for a minimum of 3 hours or more. Although gastric retention extended release dosage forms for the oral delivery of slightly soluble drugs and insoluble material have been described, gastric retention extended release dosage forms for oral administration of a polymeric active pharmaceutical ingredient (API) such as a bile acid sequestrant have not been described.

[0061] It is an object of the present invention to provide an oral dosage form that is capable of delivering prolonged and stable levels of a bile acid sequestrant to the stomach at concentrations that allow optimal binding of bile acids refluxed from the small intestine into the stomach, thereby preventing bile acid damage to the stomach lining, as well as preventing backflow of stomach bile acids into the esophagus and other parts of the upper GI and throat, preventing further damage.

[0062] Transit time through the intestinal tract often limits the amount of a drug that is available for delivery to its most efficient site of action. To counter this problem, oral administration of sparingly soluble drugs usually involves frequent dosing, often 3 or more times a day. Furthermore, drugs that are insoluble cannot readily be delivered either by solution diffusion or by membrane controlled drug delivery systems. In contrast, the inventors have observed that gastric retention, edible dosage forms of polymeric bile acid sequestrants allow for prolonged delivery of bile acid sequestrants to the stomach, where they can more efficiently bind excess bile acids than would otherwise way, they could be free of reflux in the esophagus and other areas of the upper GI and throat.

[0063] In a first aspect, the invention is a gastric retention oral dosage form for sustained release of a bile acid sequestrant to the stomach for the treatment of an upper gastrointestinal tract disease, wherein said dosage form comprises a bile acid sequestrant dispersed in a polymeric matrix, wherein the polymeric matrix comprises at least one hydrophilic polymer such that, upon inhibition of gastric fluid, said dosage form swells to a size sufficient to promote gastric retention by a period of time of 3 hours or more and wherein the bile acid sequestrant is released from the dosage form by erosion of the polymer matrix over an extended period of time.

[0064] The extended release oral dosage form provided herein gradually wears out, being held at the same time in the stomach for a period of several hours with erosion commencing upon contact with gastric fluid and the active ingredient being released into the stomach at a rate that depends on the rate of erosion of the polymer matrix.

[0065] In certain embodiments, the bile acid sequestrant is selected from cholestyramine (i.e., QUESTRAN®, QUESTRAN LIGHT®, CHOLYBAR®, CA Registry No. 11041-12-6), colesevelam (i.e., WELCHOL®, CA Registry Nos. 182815-43-6 and 182815-44-7), Selevamer (Rinogel®) and Colestipol (i.e. COLESTID®, CA Registry Nos. 50925-796 and 37296-80-3) or any other of their pharmaceutically acceptable salts or mixtures thereof. In other embodiments, the bile acid sequestrant is selected from colesevelam or colesevelam hydrochloride. In still other embodiments, the bile acid sequestrant is Selevamer.

[0066] The bile acid sequestrants described herein can be incorporated into an expendable controlled release polymer matrix device. By an "exhaustible matrix" is meant an aqueous or water swellable or aqueous soluble expendable in the sense of being both expendable and swellable or soluble (or combinations of these properties) in pure water or requires the presence of an acid or base to ionize the matrix. polymeric enough to cause erosion or dissolution (eg gastric fluid).

[0067] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the subject treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 100 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material that may range from about 5 to about 95% of the total compositions (weight: weight).

[0068] In some embodiments, the gastric retention oral dosage forms of the invention comprise a dose of bile acid sequestrant between 100 and 750 mg. In other embodiments, the dose of bile acid sequestrant in a gastric retention oral dosage form of the invention is between about 400 mg and about 600 mg. In still other embodiments, the dose of bile acid sequestrant is said gastric retention oral dosage form is about 500 mg.

[0069] In some embodiments, the gastric retention oral dosage forms of the invention comprise an amount of the bile acid sequestrant that is up to 75% of the weight of the total composition (weight:weight). In other embodiments, the amount of the bile acid sequestrant is up to 50% of the weight of the total composition (weight:weight).

[0070] When in contact with the aqueous environment of use (eg, gastric fluid), the expendable polymer matrix inhibits water and forms a gel or aqueous swollen matrix that traps the bile acid sequestrant. The aqueous swollen matrix gradually erodes, swells, disintegrates and/or dissolves in the environment of use, thereby controlling the release of the bile acid sequestrant to the environment of use.

[0071] An essential ingredient of this water-swollen matrix is at least one hydrophilic, water-swellable, wearable or soluble polymer which generally can be described as an "osmopolymer", "hydrogel" or "water-swellable" polymer. More than one such polymer can be combined in a dosage form of the invention in order to achieve gastric retention as well as the desired erosion rate.

[0072] The terms “hydrophilic” and “hydrophobic” are generally defined in terms of a partition coefficient P, which is defined as the ratio of the equilibrium concentration of a compound in an organic phase to that in an aqueous phase. A hydrophilic compound has a P value of less than 1.0, typically less than about 0.5, where P is the partition coefficient of the compound between octanol and water. A hydrophobic compound will generally have a P value greater than about 1.0, typically greater than about 5.0. The polymeric carriers herein are hydrophilic and thus are compatible with aqueous fluids such as those present in the human body, in particular the stomach.

[0073] The term "polymer", as used herein, refers to a molecule containing a plurality of covalently attached monomer units and includes branched, dendritic and star polymers as well as linear polymers. The term includes both homopolymers and copolymers, for example random copolymers, block copolymers and graft copolymers, as well as non-crosslinked polymers and slightly to moderately substantially crosslinked polymers, as well as two or more interpenetrating crosslinked networks.

[0074] The term "swellable polymer", as used herein, refers to a polymer that will swell in the presence of a fluid. It is understood that a given polymer may or may not swell when present in a defined drug formulation. Thus, the term "swellable polymer" defines a structural characteristic of a polymer that depends on the composition in which the polymer is formulated. Whether or not the polymer swells in the presence of fluid will depend on numerous factors including the specific type of polymer and the percentage of polymer in a particular formulation.

[0075] The terms "swellable" or "bioexpendable" (or simply "expendable") are used to refer to the polymers used in the present dosage forms, with "swellable polymers" being those capable of absorbing water and physically swelling as a result, to the extent that a polymer can swell, being determined by molecular weight or degree of cross-linking (for cross-linked polymers) and “bio-wearable” or “wearable” polymers referring to polymers that slowly dissolve and/or gradually hydrolyze into a aqueous fluid, and/or that physically disentangle or undergo chemical degradation of the chains themselves, as a result of movement in the stomach or GI tract. Some hydrophilic polymers have the property of being both intumescent and wearable simultaneously. Other hydrophilic polymers are only wearable.

[0076] Polymers suitable for achieving the desired gastric retention sustained release profiles of the dosage forms of the invention have the property of swelling as a result of the gastric fluid submerging in water and gradually wearing away over a time period of several hours. Since polymer wear results from fluid interaction with the dosage form surface, wear starts more or less simultaneously with the swelling process. Although wear and swelling can occur at the same time, the rate at which maximum swelling is achieved must be greater than the rate at which the dosage form completely wears out to achieve the desired release profile.

[0077] Such polymers can be linear, branched or cross-linked. The polymers can be homopolymers or copolymers.

[0078] The term "polyethylene oxide" or "PEO" refers to a polyethylene oxide polymer that has a wide range of molecular weights. PEO is a linear polymer of unsubstituted ethylene oxide and has a wide range of viscosity-average molecular weights. Examples of commercially available PEOs and their approximate molecular weights (in grams/mol or Daltons) are: POLIOX® NF, coagulant grade WSR, approximate molecular weight 5 million; POLIOX® grade WSR 301, approximate molecular weight 4 million; POLIOX® grade WSR 303, approximate molecular weight 7 million; POLIOX® grade WSR N60-K, approximate molecular weight 2 million; POLIOX® grade WSR N-80K, approximate molecular weight 200,000.

[0079] In one embodiment, at least one of the one or more hydrophilic polymers of the gastric retention oral dosage form described herein is a swellable, expendable polymer.

[0080] In some embodiments, said polymer is a polyalkylene oxide. In some embodiments, at least one of the one or more hydrophilic polymers is a polyethylene oxide (PEO). In still other embodiments, at least one hydrophilic polymer is a polyethylene oxide having a molecular weight of about 2,000,000 to 4,000,000 Daltons.

[0081] In some embodiments, the poly(ethylene oxide) is present in the unit dosage form in an amount ranging from 40 weight percent ratio to 75 weight percent ratio. In some embodiments, the poly(ethylene oxide) is present in the unit dosage form in an amount ranging from 40 weight percent ratio to 60 weight percent ratio. In some embodiments, the poly(ethylene oxide) is present in the unit dosage form in an amount ranging from 45 weight percent ratio to 55 weight percent ratio. In some embodiments, the poly(ethylene oxide) is present in the unit dosage form in an amount ranging from 45 weight percent ratio to 60 weight percent ratio. In some embodiments, the poly(ethylene oxide) is present in the unit dosage form in an amount ranging from 40 weight percent ratio to 50 weight percent ratio. In some embodiments, the poly(ethylene oxide) is present in the unit dosage form in an amount ranging from 50 weight percent ratio to 60 weight percent ratio. In some embodiments, the poly(ethylene oxide) is present in the unit dosage form in an amount ranging from a weight percent ratio to a weight percent ratio.

[0082] In other embodiments, at least one hydrophilic polymer of the dosage form is a cellulose. In certain embodiments, the polymers can be synthetic polymers derived from vinyl, acrylate, methacrylate, urethane, ester and oxide monomers. In other embodiments, they may be derived from naturally occurring polymers such as polysaccharides (e.g. chitin, chitosan, dextran and pullulan; guar gum, arabic gum, karaya gum, locust bean gum, tragacanth gum, carrageenans, ghatti gum, guar, xanthan gum and scleroglucan), starches (e.g. dextrin and maltodextrin, unmodified or pregelatinized corn starch), hydrophilic colloids (e.g. pectin), phosphatides (e.g. lecithin), alginates (e.g. ammonium alginate, sodium, potassium or calcium alginate, propylene glycol alginate), gelatin, collagen and cellulosics. Cellulosics are polymers of cellulose that have been modified by reacting at least a portion of the hydroxyl groups on the saccharide repeating units with a compound to form an ester-linked or ether-linked substituent. For example, cellulosic ethyl cellulose has an ether-linked ethyl substituent attached to the saccharide repeat unit, while cellulosic cellulose acetate has an ester-linked acetate substituent.

[0083] In certain embodiments, cellulosics for the expendable matrix comprise aqueous soluble cellulosics and aqueous expendables may include, for example, methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) ), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT) and ethyl hydroxy ethyl cellulose (EHEC). In certain embodiments, the cellulosics comprise various grades of low viscosity (MW less than or equal to 50,000 Daltons, for example, the Dow Methocel™ series E5, E15LV, E50LV and K100LY) and high viscosity (MW greater than 50,000 Daltons, for example, E4MCR, E10MCR, K4M, K15M and K100M and the Methocel™ K) HPMC series. Other commercially available types of HPMC include the Shin Etsu Metolose 90SH series.

[0084] Other materials used as the wearable matrix material include, but are not limited to, pullulan, polyvinyl pyrrolidone (povidone), polyvinyl alcohol, polyvinyl acetate, fatty acid esters of glycerol, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or acid methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, New Jersey) and other acrylic acid derivatives such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate and (trimethylaminoethyl)methacrylate chloride .

[0085] In some embodiments, the hydrophilic polymer is used as a binder in the unit dosage form and is selected from povidone, starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

[0086] In certain embodiments, the pharmaceutical dosage form is retained in the stomach for a period of 3 to 24 hours (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours). For the purposes of this description, when the term “at least X hours” is used, the term shall mean X hours to 24 hours inclusive; to be perfectly clear, the term “at least 3 hours” must mean 3 hours to 24 hours inclusive. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 3 hours. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 4 hours. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 6 hours. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 7 hours. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 8 hours. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 10 hours. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 11 hours. In some embodiments, the pharmaceutical dosage form is retained in the stomach for at least 12 hours.

[0087] The polymer matrix wears out in the stomach during a period of drug release. For the purposes of this description, when the term “at least X hours” is used, the term shall mean X hours to 24 hours inclusive; to be perfectly clear, the term “at least 3 hours” must mean 3 hours to 24 hours inclusive. In some embodiments, the drug release period is at least four hours. In some embodiments, the drug release period is at least six hours. In some embodiments, the drug release period is at least eight hours. In some embodiments, the drug release period is at least ten hours. In some embodiments, the drug release period is at least eleven hours. In some embodiments, the drug release period is at least twelve hours. In some embodiments, the polymer matrix wears out in the stomach during a period that begins after drug release has begun. Wear may not occur during the full drug release period. For example, at time points prior to the matrix swelling, some drug release will occur on the basis of swelling with minimal wear.

[0088] The drug release rate from the gastric retention dosage form described herein can be measured in vitro in acetate buffer at pH 4.5, using a USP Type II apparatus (paddle) with the tablets placed on platinum. In some embodiments, between 30 to 85% of the drug has been released from the dosage form after 10 hours. In some embodiments, between 50 to 85% of the drug has been released from the dosage form after 10 hours. In some embodiments, between 60 to 85% of the drug has been released from the dosage form after 10 hours. In some embodiments, between 65 to 85% of the drug has been released from the dosage form after 10 hours. In some embodiments, between 70 to 85% of the drug has been released from the dosage form after 10 hours. In some embodiments, between 75 to 100% of the drug has been released from the dosage form after 12 hours. In some embodiments, between 75 to 100% of the drug has been released from the dosage form after 16 hours. In some embodiments, between 85 to 100% of the drug has been released from the dosage form after 12 hours. In some embodiments, between 85 to 100% of the drug has been released from the dosage form after 16 hours. In some embodiments, between 80 to 100% of the drug has been released from the dosage form after 20 hours. In some embodiments, between 90 to 100% of the drug has been released from the dosage form after 20 hours. In some embodiments, about 90 to 100% of the drug has been released from the dosage form after 24 hours.

[0089] In certain embodiments, the oral dosage of gastric retention swells to a size that is at least 110% of the original size within 30 minutes. In other embodiments, it swells to a size that is at least 130% of its original size within 2 hours. In other embodiments, it swells to a size that is at least 140% of its original size within 2 hours.

[0090] In some embodiments, the gastric retention oral dosage form comprises two polymers, both of which are swelling polymers and expendable hydrophilic. In some embodiments, the first of said polymers is a PEO and the second of said polymers is a cellulose.

[0091] In some embodiments, the gastric retention oral dosage form comprises two polymers, one being a wearable hydrophilic swelling polymer and the other being a wearable non-hydrophilic swelling polymer. In some embodiments, the swelling and expendable hydrophilic polymers are selected from a PEO or a cellulose. In some embodiments, the non-wearable, non-hydrophilic swelling polymer is selected from 600 mg PolyOx Coag, methylcellulose, hydroxypropylmethylcellulose, and hydroxypropylcellulose.

[0092] In still other embodiments, the gastric retention oral dosage form comprises two polymers, one being a wearable hydrophilic swelling polymer and the other being a wearable non-hydrophilic swelling polymer. In some embodiments, the expendable hydrophilic swelling polymer is selected from a PEO or a cellulose. In some embodiments, the expendable non-hydrophilic swelling polymer is selected from ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose acetate succinate, or Eudragit RSPO.

[0093] In certain embodiments, the dosage form may additionally contain suitable diluents, glidants, lubricants, acidulants, stabilizers, fillers, binders, plasticizers or release aids and other pharmaceutically acceptable excipients.

[0094] In some embodiments, the gastric retention oral dosage form of the invention comprises a filler or blowing agent selected from microcrystalline cellulose, lactose, starch, maltodextrins and dibasic calcium phosphate. In other embodiments, the filler or compressing agent is a microcrystalline cellulose.

[0095] In some embodiments, the gastric retention oral dosage form of the invention comprises a glidant selected from silicon dioxide and talc.

[0096] In some embodiments, the gastric retention oral dosage form of the invention comprises a lubricant selected from magnesium stearate, stearic acid, sodium stearyl fumarate. In other embodiments, the lubricant is magnesium stearate.

[0097] In some embodiments, the gastric retention oral dosage form of the invention is composed of a core and a shell. In some embodiments, the coating represents between 5% and 7.5% of the total formulation weight (weight:weight).

[0098] In some embodiments, the coating is composed of a binder and a plasticizer. In some embodiments the plasticizer is an acetylated glyceride. In some embodiments, the binder is selected from hydroxypropylmethylcellulose, CAP, HPMCAS, HPMCP, or ethylcellulose.

Dosage form preparation

[0099] In a second aspect, the present discussion pertains to a method for manufacturing a gastric retention sustained release dosage form comprising at least one bile acid sequestrant, such as those described in the previous section.

[00100] The active agents used in the dosage forms of the present disclosure can be formulated according to methods that are standard in the art (see, for example, Remington: the Science and Practice of Pharmacy 21st Ed. 2005, University Sciences in Philadelphia Pa. .) or Developing Solid Oral Dosage Forms - Pharmaceutical Theory and Practice, 1st Ed; Academic Press; Burlington, MA.

[00101] During the process, the drug can be mixed with excipients, carriers, buffers, conventional flavoring agents, etc. Typical carriers include, but are not limited to: water; salt solutions; alcohols; arabic gum; vegetable oils; benzyl alcohols; polyethylene glycols; gelatin; carbohydrates such as lactose, amylose or starch; magnesium stearate; baby powder; silicic acid; paraffin; perfume oil; fatty acid esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc. Pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents such as: lubricants; preservatives; disintegrants; stabilizers; wetting agents; emulsifiers; salts; tampons; natural or artificial coloring agents; natural or artificial flavoring agents; or aromatic substances.

[00102] Tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the active ingredient in powder form moistened with an inert liquid diluent. Standard methods for tablet preparation include direct compression, dry granulation with roller compaction, dry granulation with lump formation and wet granulation. These methods are well known to those skilled in the art.

[00103] “Granulation”, as used herein, is defined as the process in which primary powdery particles are made to adhere to form larger, multi-particle entities called granules. It is the process of collecting particles together by creating bonds between them. Bonds are formed by comparison (“dry granulation”) or using a binding agent (“wet granulation”). Granulation is extensively used in tablet manufacturing. The granulation process usually combines one or more powder particles and forms a granule that will allow the compression process to be within the required limits. In this way, a predictable and repeatable process is possible and the quality of tablets or precipitates can be produced using compression equipment.

[00104] Dry granulation can be conducted in two processes; either a large tablet (“chunk”) is produced in a heavy powder compression press (“chunk forming”) or the powder is squeezed between two rolls to produce ribbons of materials (“roll compaction”). These materials (i.e. chunks or ribbons) are then crushed to provide "granules".

[00105] In accordance with the invention, when ingredients are incorporated prior to granulation, they are referred to as "intragranular", i.e. in the granule. When ingredients are incorporated after granulation, they are referred to as “extragranular”.

[00106] The enteric coating that surrounds the core can be applied using standard coating techniques. Materials used to form the enteric coating may be dissolved or dispersed in organic or aqueous solvents and may include one or more of the following: methacrylic acid copolymers; shellac; hydroxypropylmethylcellulose phthalate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose trimellitate; carboxymethylcellulose; cellulose acetate phthalate; or other suitable enteric coating polymers. The pH at which the enteric coating will dissolve can be controlled by the polymer or polymer combination selected and/or ratio of pendant groups. For example, coating dissolution characteristics can be altered by the ratio of free carboxyl groups to ester groups. Enteric coating layers may also contain pharmaceutical plasticizers such as: triethyl citrate; dibutyl phthalate; triacetin; polyethylene glycols; polysorbates; acetylated glycerides, etc. Additives such as dispersing agents, coloring agents, non-sticks, taste masking and anti-foaming agents may also be included.

[00107] In some embodiments, the coating of the unit dosage form of the invention comprises a microcrystalline cellulose and an acetylated glyceride.

[00108] In some embodiments, the gastric retention sustained release dosage forms of the invention can be prepared by a process as described below. Intragranular components are combined and mixed to form an intragranular mixture. In some cases, the bile acid sequestrant (active ingredient) is one of the intragranular components. Intragranular components may additionally include fillers or compression aids such as microcrystalline cellulose and/or lubricants such as magnesium stearate. The intragranular mixture is compressed into the pieces and the pieces are ground to form crushed granulation. The yield for the ground granulation is calculated so that the desired amounts of the extragranular components to be used can be determined. Extragranular components are combined and blended to form an extragranular mixture. In some cases, the hydrophilic polymer is one of the extragranular components. There may be more than one hydrophilic polymer present. In some cases, the hydrophilic polymer may be composed of polyalkylene oxide, such as polyethylene oxide. Extragranular components can include fillers or compression aids, such as microcrystalline cellulose; binders or drug delivery aids, such as trehalose or hydroxypropyl methylcellulose; plasticizers such as diacetylated monoglyceride; and/or lubricants, such as magnesium stearate. The extragranular components and ground granulation are then combined and blended to form a dry blend. Extragranular components can be blended and blended at any time prior to blending with the crushed granulation; that is, the extragranular components may be blended and mixed before the intragranular components are blended and blended or vice versa.

[00109] In some embodiments, the dry mixture may be compressed into one or more tablets. In other embodiments, the tablets may be coated with an outer layer (coating). In some embodiments, the coating may be 3:1 HPMC (Grade - E50 Premium LV): diacetylated monoglycerides, NF Grade-(Myvacet 9-45K).

[00110] The dosage forms of the invention can be packaged for use in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container with the pharmaceutical dosage form deposited therein. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The container may also include an anti-counterfeiting assembly to prevent indiscreet access to the contents of the package. Furthermore, the container has a label deposited thereon which describes the contents of the container. The label may also include appropriate warnings.

therapeutic methods

[00111] In a third aspect, the gastric retention extended release oral dosage forms comprising at least one bile acid sequestrant that are described herein are used to treat upper gastrointestinal (GI) and throat disorders. In some cases, upper GI disorders are esophageal disorders. In certain embodiments, the patient may suffer from (or be susceptible to developing) an upper GI tract or throat disorder selected from one or more of: gastroesophageal reflux disease or GERD, including unresponsive GERD; Barrett's esophagus; esophageal cancer, gastritis, heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, gastric cancer, esophageal ulcer, esophagitis, laryngitis, pharyngitis, hoarse voice, and GERD-related lung dysfunction such as cough and/or asthma. In some embodiments, the upper GI tract or throat disorder is GERD or dyspepsia. In some embodiments, the upper GI tract or throat disorder is GERD. In some embodiments, the upper GI tract or throat disorder is dyspepsia.

[00112] As used herein “Unresponsive GERD” refers to chronic reflux disorders that do not respond to current therapies to treat such conditions. Such therapies include, for example, administration of proton pump inhibitors, H2 blockers and various antacids which are well known in the art.

[00113] In some embodiments, a method of administering a therapeutically effective amount of a daily dosage of 100 mg to 4000 mg of a bile acid sequestrant to a subject in need thereof is described. In some embodiments, the daily dosage of a bile acid sequestrant is 100 mg to 2500 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 500 mg to 4000 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 500 mg to 2500 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 1000 mg to 4000 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 1000 mg to 3000 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 2000 mg to 4000 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 1500 mg to 3000 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 200 mg to 3000 mg. In some embodiments, the daily dosage of a bile acid sequestrant is 2000 mg to 2500 mg. In these embodiments, the subject is administered the gastric retention oral dosage form described herein when the subject is in the fed state.

[00114] In some embodiments, the dose of bile acid sequestrant described herein is administered up to 4 times in a 24 hour period. In other modalities, it is administered up to 3 times in a 24-hour period. In other embodiments, it is given 1 or 2 times a day. In still other embodiments, it is administered once a day.

[00115] In some embodiments, the dose of bile acid sequestrant described herein is administered with one or more meals. In some embodiments, the dose of bile acid sequestrant described herein is administered at bedtime. In some embodiments, the dose of bile acid sequestrant described herein is administered with one or more meals and at bedtime. In some embodiments, the dose of bile acid sequestrant described herein is administered before or after one or more meals. In some embodiments, the dose of bile acid sequestrant described herein is administered with a meal. In some embodiments, the dose of bile acid sequestrant described herein is administered within 30 minutes after a meal. In some embodiments, the dose of bile acid sequestrant described herein is administered up to 5 minutes before a meal.

[00116] In some embodiments, the invention is a method of treating or preventing an upper gastrointestinal tract or throat disorder or symptom by administering to a patient in need thereof a dosage form described herein.

[00117] In some embodiments, the use of a gastric retention oral dosage form described herein for sustained release of a bile acid sequestrant to the stomach for the treatment of an upper gastrointestinal tract or throat disease is described.

[00118] In some embodiments, there is described a gastric retention oral dosage form described herein for use in treating a subject suffering from a selected disease of heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, esophageal ulcers , esophagitis, laryngitis, pharyngitis, hoarse voice, gastroesophageal reflux disease (GERD), Barrett's esophagus, gastric cancer, esophageal cancer (eg, adenocarcinoma), gastritis, and GERD-related lung dysfunction. In some embodiments, a total daily dosage of from about 100 mg to about 4000 mg of a bile acid sequestrant in the form of the gastric retention oral dosage form is administered to the subject.

[00119] The terms, "disease", "disorder" and "condition" may be used interchangeably herein to refer to a medical or pathological condition or symptom believed to be the result of bile reflux.

[00120] As used herein, the terms “individual” and “patient” are used interchangeably. The terms "individual" and "patient" refer to an animal (e.g. a bird such as a chicken, quail or turkey or a mammal), specifically a "mammal" including a non-primate (e.g. a cow , pig, horse, sheep, rabbit, guinea pig, rat, cat, dog and mouse) and a primate (eg a monkey, chimpanzee and a human) and more specifically a human. In some embodiments, the individual is a non-human animal, such as a farm animal (eg, a horse, cow, pig, or sheep) or a domestic animal (eg, a dog, cat, guinea pig, or rabbit) . In some embodiments the individual is a human.

[00121] A “susceptible individual” or “a patient in need thereof” is an individual who suffers from, is suffering from, or is likely or predisposed to suffer from an upper GI or throat disorder believed to result from bile reflux. In humans and as used herein, these conditions may include, for example, heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, esophageal ulcers, esophagitis, laryngitis, pharyngitis, hoarse voice, and GERD-related lung dysfunction such as such as cough and/or asthma. Additional complications believed to occur as a result of bile reflux are, for example, gastroesophageal reflux disease or GERD; Barrett's esophagus; esophageal cancer (eg, adenocarcinoma) and gastritis. In animals these conditions may include, for example, peptic ulcer of the stomach.

[00122] The term "biological sample", as used herein, refers to an in vitro or ex vivo sample and includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, lymph fluid, eye fluid, vitreous humor or other body fluids or extracts thereof.

[00123] "Treating", "treating" or "treatment" with respect to a disorder or disease refers to alleviating or nullifying the cause and/or effects of the disorder or disease. Treatment may involve administering a compound described herein to a patient diagnosed with a disease and may involve administering the compound to a patient who does not have active symptoms. Conversely, treatment may involve administering the compositions to a patient at risk of developing a particular disease or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of that disease may not have been made.

[00124] As used herein, "treating" or "treating" a condition or individual refers to having the steps to obtain beneficial or desired results, including clinical outcomes. For purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, alleviation of one or more disease, symptom, or condition that arises as a result of bile reflux in the upper GI tract or throat.

[00125] The terms "administering", "administering" or "administering" in reference to a dosage form of the invention refer to the action of introducing the dosage form into the system of the individual in need of treatment. When a dosage form of the invention is given in combination with one or more other active agents (in their respective dosage forms), "administration" and variants thereof are each understood to include concomitant and/or sequential introduction of the dosage form and the other active agents.

[00126] Administration of any of the described dosage forms includes parallel administration, co-administration or sequential administration, in which the therapies are administered at approximately the same time, for example, within about a few seconds to a few hours of each other.

[00127] The term "fed mode", as used herein, refers to a state that is typically induced in a patient by the presence of food in the stomach, the food giving rise to two signals, one which is said to stop the stomach distention and the other a chemical signal based on food contents in the stomach. It has been determined that once the fed state is induced, larger particles are retained in the stomach for a longer period of time than smaller particles. The fed mode is induced by nutritive materials entering the stomach upon ingestion of food. Initiation from the fed state is accompanied by a rapid and profound change in upper GI tract motor pattern, over a period of 30 seconds to one minute. The change is observed almost simultaneously at all sites along the GI tract and occurs before stomach contents reach the distal small intestine. Once the fed state is established, the stomach generates 3 to 4 continuous, regular contractions per minute, similar to the fasted mode, but at about a quarter to half the amplitude (Strength). The pylorus partially opens, causing a sieving effect in which liquids and small particles continuously flow from the stomach into the intestine, while indigestible particles larger than the pyloric opening are retro-peeled and retained in the stomach. This effect causes the stomach to retain particles that exceed about 1 cm in size for approximately 4 to 8 hours or more.

[00128] Administration of a dosage form "with a meal", as used herein, refers to administration during or after ingestion of food or drink. When the dosage form is administered after a meal, it may be administered approximately 1, 2, 3, 4, 5, 10, 15, or even 30 minutes after the completion of a meal. In some embodiments, the dosage form may be administered up to 5 minutes before a meal.

[00129] In another aspect, the patient has a genetic predisposition to develop a disorder related to bile reflux. In another aspect, a dosage form described herein is administered to a patient so as to prevent or minimize damage to the upper GI tract or throat.

[00130] In one embodiment, the methods of the invention are a preventative or "preventive" measure of a patient, specifically a human, with a predisposition (e.g., a genetic predisposition) to develop a disease, disorder, or symptom that is believed to result from bile reflux.

[00131] In other embodiments, the methods of the invention are a preventative or "preventive" measure of a patient, specifically a human, suffering from a disease, disorder or condition that puts them at risk of developing a bile reflux-related disorder or symptom.

[00132] The extended release gastric retention oral dosage forms described herein are also used for veterinary treatment of companion animals, exotic animals and farm animals including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.

combination therapies

[00133] The gastric retention extended release oral dosage forms comprising at least one bile acid sequestrant described herein can be used in combination therapy with one or more additional therapeutic agents. For combination treatment with more than one active agent, where the active agents may be in separate dosage forms, the active agents may be administered separately or together. Furthermore, administration of one agent may be prior to, concurrent with, or subsequent to administration of the other agent.

[00134] As used herein, the terms "in combination" or "co-administration" may be used interchangeably to refer to the use of more than one therapy (eg, one or more prophylactic and/or therapeutic agents). Use of the terms does not restrict the order in which therapies (eg, prophylactic and/or therapeutic agents) are administered to an individual.

[00135] In some embodiments, the methods may include simultaneously, separately or sequentially administering a therapeutically effective amount of one or more proton pump inhibitors.

[00136] In other embodiments, the methods may include simultaneously, separately or sequentially administering a therapeutically effective amount of one or more acid pump antagonists.

[00137] In other embodiments, the methods may include simultaneously, separately or sequentially administering one or more agents chosen from an antacid, a histamine H2 receptor antagonist, a β agonist of Y-aminobutyric acid (GABA-B), a prodrug of a GABA-B agonist and a protease inhibitor.

[00138] When co-administered with other agents, an “effective amount” of the second agent will depend on the type of drug used. Suitable dosages are known to approved agents and can be adjusted by one of skill in accordance with the individual's condition, the type of condition(s) being treated, and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount must be considered. For example, compounds described herein can be administered to a subject in a dosage range of from about 0.01 to about 10,000 mg/kg of body weight/day, about 0.01 to about 5,000 mg/kg of body weight. body weight/day, about 0.01 to about 3000 mg/kg body weight/day, about 0.01 to about 1000 mg/kg body weight/day, about 0.01 to about 500 mg /kg body weight/day, about 0.01 to about 300 mg/kg body weight/day, about 0.01 to about 100 mg/kg body weight/day.

[00139] Although the two or more agents in combination therapy can be given simultaneously, they need not be. For example, administration of a first agent (or combination of agents) may precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18 or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable for the two or more agents used in a combination therapy to be present in the patient's body at the same time, this need not be so.

[00140] Combination therapy may also include two or more administrations of one or more of the agents used in the combination. For example, if agent X and agent Y are used in a combination, they can be administered sequentially in any combination one or more times, for example, in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

[00141] The present disclosure also relates to a method of treating or preventing an upper gastrointestinal disorder or throat disorder, which is particularly used as a first-line or initial therapy, comprising administering to a patient in need thereof a regimen combination therapy described in the kits and dosage forms provided and discussed herein. “First-line” or “initial” treatment refers to treatment in the first case after a re-diagnosis of an upper gastrointestinal disorder or after a recurrence of an upper gastrointestinal disorder after discontinuation of treatment. However, the method of treatment can be used in any patient with an upper gastrointestinal disorder that does not respond to monotherapy with PPIs or bile acid sequestrants.

[00142] PPI drugs are substituted benzimidazole compounds that specifically inhibit gastric acid secretion by affecting the H+/K+ ATPase enzyme system (the proton pump). These drugs, eg esomeprazole, are rapidly absorbed and have very short half-lives. However, they show prolonged binding to the H+/K+ ATPase enzyme. The anti-secretory effect reaches a maximum in about 4 days with once-daily dosing. Because of these characteristics, patients starting PPI therapy do not receive the maximum benefit from the drug and healing may not begin for up to 5 days after therapy begins when PPIs are used alone for initial therapy of upper GI disorders.

[00143] Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion, inhibiting H+/K+ ATPase, the enzyme involved in the final step of hydrogen ion production in parietal cells. The term proton pump inhibitor includes, but is not limited to, omeprazole (sold under the tradenames PRILOSEC®, LOSEC®, or ZEGERID®), lansoprazole (sold under the tradenames PREVACID®, ZOTON®, or INHIBITOL®), rabeprazole (sold under the tradenames PREVACID®, ZOTON®, or INHIBITOL®). under the tradename RABECID®, ACIPHEX® or PARIET®), pantoprazole (sold under the tradename PROTONIX®, PROTIUM®, SOMAC® or PANTOLOC®), tenatoprazole (also referred to as benatoprazole) and leminoprazole, including isomers, enantiomers and tautomers of these (e.g. esomeprazole (sold under the tradename NEXIUM®)), Dexlansoprazole, Dexrabeprazole, (S)-Pantoprazole, Ilaprazole and alkaline salts thereof; The following patents describe various benzimidazole compounds suitable for use in the description described herein: U.S. At the. 4,045,563, U.S. Patent At the. 4,255,431, U.S. Patent At the. 4,359,465, U.S. Patent At the. 4,472,409, U.S. Patent At the. 4,508,905, JP-A-59181277, U.S. Patent At the. 4,628,098, U.S. Patent At the. 4,738,975, U.S. Patent At the. 5,045,321, U.S. Patent At the. 4,786,505, U.S. Patent At the. 4,853,230, U.S. Patent At the. 5,045,552, EP-A-295603, U.S. Patent At the. 5,312,824, EP-A-166287, U.S. Patent At the. 5,877,192, EP-A-519365, EP5129, EP 174,726, EP 166,287 and GB 2,163,747. All prior patents are incorporated herein by reference. Thus, proton pump inhibitors and their pharmaceutically acceptable salts, which are used in accordance with the present description, are compounds and can be produced by known processes. In certain embodiments, the proton pump inhibitor is omeprazole, either in a racemic mixture or only the (-)enantiomer of omeprazole (i.e., esomeprazole), as disclosed in the U.S. patent. At the. 5,877,192, incorporated herein by reference.

[00144] Omeprazole is typically given at a 20 mg dose/day for active duodenal ulcer for 4 to 8 weeks; on a 20 mg dose/day for gastroesophageal reflux disease (GERD) or severe erosive esophagitis for 4 to 8 weeks; in a 20 mg dose/twice daily for treatment of Helicobacter pylori (in combination with other agents); on a 60 mg dose/day for active duodenal ulcer for 4 to 8 weeks and up to 120 mg three times/day and on a 40 mg dose/day for gastric ulcer for 4 to 8 weeks. Such dosages are contemplated within the scope of the present description. Thus, in certain embodiments of the present disclosure, the amount of proton pump inhibitor that is included in the dosage form is an amount that is considered to be therapeutically effective, in accordance with the dosages shown for a variety of disease states. In other embodiments of the present disclosure, the dose of proton pump inhibitor is subtherapeutic. For example, when the drug is omeprazole, the dosage form may contain from about 0.1 mg to about 120 mg of omeprazole.

[00145] Lansoprazole is typically administered at about 15 to 30 mg/day; rabeprazole is typically given 20 mg/day and pantoprazole is typically given 40 mg/day. However, any therapeutic or subtherapeutic dose of these agents is considered within the scope of the present disclosure.

[00146] Acid pump antagonists (APAs) that act by competitive and reversible binding of K(+) (as opposed to irreversible PPIs) to the gastric proton pump, which is the final step for activating acid secretion in the parietal cell. One class of APAs are the imidazopyridines. BY841 was selected from this class and is chemically a (8-(2-methoxycarbonylamino-6-methyl-phenylmethylamino)-2,3-dimethyl-imidazo[1,2-a]-pyridine). In pharmacological experiments, such as pH monitoring in the dog with a simulated conscious pentagastrin fistula, BY841 proved superior to both ranitidine and omeprazole by rapidly raising intragastric pH to a value of 6. The duration of this pH elevation in the dog was dose dependent. Using both continuous 24-hour acid output and pH measurements, a pronounced antisecretory effect of BY841 was observed. Indeed, a single 50 mg oral dose of BY841 immediately raised gastric pH to about 6. Higher doses caused a dose-dependent increase in the duration of the pH elevation, with no further increase in maximal pH values. Twice-daily administration was more effective than once-daily administration of the same daily dosage. With both regimens, the duration of the pH-raising effect of BY841 was further increased upon repeated daily administration. This demonstrates a lack of tolerance development, the latter being a well-known disadvantage of H2 receptor antagonists. Compared to the standard dose of omeprazole, BY841 given at a dose of 50 mg or 100 mg twice daily is markedly more effective on Day one of treatment and both doses are at least as potent as omeprazole after repeated daily dosing.

[00147] Examples of some APAs that could be used in the methods of the invention include, but are not limited to: BY-841 (Prumaprazole), Sch-28080, YJA-20379-8, YJA-20379-1, SPI-447, SK&F- 97574, AU-2064, SK&F-96356, T-330, SK&F-96067, SB-641257A (YH-1885, Revaprazan hydrochloride, RevanexR), CS-526, R-105266, Linaprazan, Sorapraza, DBM-819, KR -60436, RQ-00000004 (RQ-4) and YH-4808.

[00148] The oral dosage forms described herein may also be administered in conjunction with other agents to treat the gastrointestinal tract, such as histamine H2 receptor blockers, motility agents (gastroprokinetics), antacids, anti-ulcer agents, β acid agonists. Y-aminobutyric acid (GABA-B), prodrugs of GABA-B agonists, GCC agonists and/or protease inhibitors. Non-limiting examples of these additional agents include those selected from the group consisting of cinitapride, cisapride, fedotozine, loxiglumide, sodium alexitol, almagate, aluminum hydroxide, aluminum magnesium silicate, aluminum phosphate, azulene, basic aluminum carbonate gel , bismuth aluminate, bismuth phosphate, bismuth subgallate, bismuth subnitrate, calcium carbonate, dihydroxyaluminum aminoacetate, sodium dihydroxyaluminum carbonate, ebimar, magaldrate, magnesium hydroxide and carbonate, magnesium hydroxide, sodium oxide magnesium, magnesium peroxide, magnesium phosphate (tribasic), magnesium silicates, potassium citrate, sodium bicarbonate, aluminum aceglutamide complex, acetoxolone, aldioxa, arbaprostil, benexate hydrochloride, carbenoxolone, cetraxate, cimetidine, colloidal bismuth subcitrate, ebrotidine, ecabet, enprostila, esaprazole, famotidine, gefamate, guaiazulene, irsogladine, misoprostol, nizatidine, omoprostila, Y-Oryza nol, pifamine, pirenzepine, plaunotol, polaprezinc, ranitidine, rebamipide, rioprostil, rosaprostol, rotraxate, roxatidine acetate, sofalcone, spirofarone, sucralfate, telenzepine, teprenone, trimoprostil, trithiozine, troxipide, zolimidine, baclofen, R-baclofen, XP19986 (CAS At the. registration 847353-30-4), pepstatin and other pepsin inhibitors (eg sodium benzoate); and chymotrypsin and trypsin inhibitors. A wide variety of trypsin and chymotrypsin inhibitors are well known to those skilled in the art and can be used in the methods described herein. Such trypsin and chymotrypsin inhibitors may include tissue factor pathway inhibitor; α-2 antiplasmin; members of the α-1 antichymotrypsin serpin family; jelly; hirustasin; eglins including eglin C; Bombyx mori inhibitors (see; for example; JP 4013698 A2 and JP 04013697 A2; CA Registry No. 142628-93-1); hirudin and variants thereof; leukocyte inhibitory protease inhibitor (SLPI); α-1 antitrypsin; Bowman-Birk protease inhibitors (BBIs); chymotrypsin inhibitors represented by CAS nos. 306762-66-3, 306762-67-4, 306762-68-5, 306762-69-6, 306762-70-9, 306762-71-0, 306762-72-1, 306762-73-2, 306762-74-3, 306762-75-4, 178330-92-2, 178330-93-3, 178330-94-4, 81459-62-3, 8145979-2, 81460-01-7, 85476-59- 1, 85476-62-6, 85476-63-7, 85476-67-1, 8547670-6, 85858-66-8, 85858-68-0, 85858-69-1, 85858-70-4, 85858- 71-5, 8585872-6, 85858-73-7, 85858-75-9, 85858-77-1, 85858-79-3, 85858-81-7, 8585883-9, 85858-84-0, 85858- 85-1, 85858-87-3, 85858-89-5, 85858-90-8, 8585892-0, 85879-03-4, 85879-05-6, 85879-06-7, 85879-08-9, 85858-74-8, 9018624-6, 90185-93-6, 89703-10-6, 138320-33-9 (YS3025), 94149-41-4 (MR889), 85858-76-0, 89703-10- 6, 90185-92-5, 90185-96-9, 90185-98-1, 90186-00-8, 90186-01-9, 90186-05-3, 90186-06-4, 90186-07-5, 90186-08-6, 90186-09-7, 90186-10-0, 90186-11-1, 90186-12-2, 90186-13-3, 90186-14-4, 90186-22-4, 90186- 23-5, 90186-24-6, 90186-25-7, 90186-27-9, 90186-28-0, 90186-29-1, 90186-31-5, 90186-35-9, 90186-43- 9, 90209-88-4, 90209-89-5, 90209-92-0, 90209-94-2, 902 09-96-4, 90209-97-5, 90210-01-8, 90210-03-0, 90210-04-1, 90210-25-6, 90210-26-7, 90210-28-9, 90230- 84-5, 90409-84-0, 95460-86-9, 95460-87-0, 95460-88-1, 95460-89-2, 95460-91-6, 114949-00-7, 114949-01- 8, 114949-02-9, 114949-03-0, 114949-04-1, 114949-05-2, 114949-06-3, 114949-18-7, 114949-19-8, 114964-69-1, 114964-70-4, 9076-44-2 (chymostatin), 30827-99-7 (Pefabloc), 618-39-3 (benzamidine), 80449-31-6 (urinistatin), 130982-43-3, 197913- 52-3, 179324-22-2, 274901-16-5, 792163-40-7, 339169-59-4, 243462-36-4, 654671-78-0, 55123-66-5 (leupeptin), 901 -47-3, 4272-74-6, 51050-59-0, 221051-66-7, 80449-31-6, 55-91-4, 60-32-2, 88070-98-8, 87928-05 -0, 402-71-1 (benzenesulfonamide), 139466-47-0, CI-2A (see US5167483), CI-2A (seebWO9205239), WCI-3 (see Shibata et al. 1988 J Biochem (Tokyo) 104:537-43), WCI-2 (see Habu et al. 1992 J Biochem (Tokyo) 111:249-58) and WCI-x (Habu et al., supra) and 178330-95 -5; and compounds with chymotrypsin inhibiting activity described in patent applications JP 56092217 A2, US4755383, US4755383, US4639435, US4620005, US4898876 and EP0128007.

[00149] Examples of other therapeutic agents that can be combined with a compound of this disclosure, either administered separately or in the same pharmaceutical composition include, but are not limited to, linaclotide, IW-9179, plecanatide and SP-333.

kits

[00150] In a fourth aspect, kits for treating an upper GI tract or throat disorder comprising, in one or more containers, a therapeutically effective amount of a bile acid sequestrant in the form of gastric retention extended release dosage forms herein described and a label or packaging insert containing instructions for use are described.

[00151] The compounds and pharmaceutical formulations described herein may be contained in a kit. The kit may include single or multiple doses of two or more agents, each individually packaged or formulated, or single or multiple doses of two or more agents packaged or formulated in combination. Thus, one or more agents may be present in the first container and the kit may optionally include one or more agents in a second container. The container or containers are placed in a package and the package may optionally include administration or dosage instructions. A kit may include additional components, such as syringes or other means for administering the agents, as well as diluents or other means for formulation. Thus, kits may comprise: a) a dosage form described herein (one or more than one unit to constitute the necessary therapeutic dosage); and b) a container or package. Kits may optionally comprise instructions that describe a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g., preventing or treating one or more of the diseases and disorders described herein). The kit may optionally comprise a second pharmaceutical composition comprising one or more additional agents described herein for use in cotherapy, a pharmaceutically acceptable carrier, vehicle or diluent.

[00152] A kit includes a container or package for containing the pharmaceutical compositions and may also include divided containers, such as a divided bottle or a divided foil pack. The container can be, for example, a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (for example, to keep a “refill” of pills to put in a different container) or a pack of ampoule with individual doses to press the package according to a therapeutic schedule. It is possible that more than one container may be used together in a single package to market a single dosage form. For example, pills may be contained in a bottle, which in turn is contained in a box.

[00153] An example of a kit is a so-called ampoule pack. Ampoule packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules and the like). Ampoule packs generally consist of a sheet of relatively rigid material covered with a sheet of a preferably transparent plastic material. During the packaging process, indentations are formed in the plastic sheet. The indentations are sized and shaped as individual tablets or capsules to be packaged or may be sized and shaped to accommodate multiple tablets and/or capsules to be packaged. Then the tablets or capsules are placed in the indentations in this manner and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet, which is opposite the direction in which the indentations were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the indentations between the plastic sheet and the foil. Preferably the strength of the blade is such that the tablets or capsules can be removed from the ampoule manually by applying pressure to the indentations, while an opening is formed in the blade at the place of the indentation. The tablet or capsule can then be removed through said opening.

[00154] It may be desirable to provide information and/or instructions containing written memory aids to the physician, pharmacist or individual as to when medication should be taken. A “daily dosage” can be a single pill or several pills to be taken in a given day. When the kit contains separate compositions, a daily dosage of one or more kit compositions may consist of one tablet or capsule, while a daily dosage of one or more other kit compositions may consist of several tablets or capsules. A kit may take the form of a dispenser designed to dispense the daily dosages one at a time in the order of their intended use. The dispenser may be equipped with a memory aid so as to further facilitate adherence to the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled with a liquid crystal readout mode or audible reminder signal that, for example, reads data from the last daily dose that was taken and/or reminds you when the next dose is due.

[00155] These and other objects, features and advantages of this description will become evident from the following detailed description of the various aspects of the description in conjunction with the attached examples.

EXAMPLES

[00156] All references provided in the examples are hereby incorporated by reference in full. As used herein, all abbreviations, symbols, and conventions are consistent with those used in modern scientific literature. See, for example, Janet S. Dodd, ed., The ACS Stile Guide: A Manual for Authors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997, incorporated herein by reference in its entirety.

Example 1: Procedure for manufacturing large-scale batches 1. Intragranular mix

[00157] Intragranular components (except magnesium stearate) were dispensed and passed through a 20 mesh sieve. Components were added to a V-blender and blended for 10 minutes at 25 RPM. Intragranular magnesium stearate was then dispensed and passed through a 20 mesh sieve. Magnesium stearate was added to the V-blender and blended for 2 minutes at 25 RPM.

[00158] The resulting intragranular mixture was discharged from the V-blender.

2. Piece formation

[00159] A 24-station Fettle tablet press was equipped with eight 0.6250'' round bottom, type B flat face machining elements. The intragranular steel obtained above was added to the funnel of the tablet press. Using a tablet press tower speed of 15 to 25 RPM, the blend was compressed into pieces with a target weight of 1200 to 1400 mg and a hardness of 9 to 15 kp. In-process checks were performed during piece formation regarding appearance, weight, hardness and thickness.

3. Crushing

[00160] A Quadro Comil apparatus equipped with eight of the sieves (2C125G03723390 - 0.125” hole size or 2C 109G03727333 - 0.109” hole size) and a straight impeller (square). The pieces obtained previously were transferred to the funnel of the Quadro Comil apparatus. The pieces were ground at 2000 RPM and the ground granulation recovered. The yield for the recovered granulation was calculated.

4. Extragranular mix

[00161] The required amounts of the extragranular components were determined based on the yield of the crushed granulation step. The extragranular components (except magnesium stearate) were then dispensed and passed through a 20 mesh sieve. A portion of the ground granulation was added to a V-blender. The dispensed extragranular components were then added to the V-blender and blended for 10 minutes at 25 RPM. The extragranular magnesium stearate was then dispensed and passed through a 20 mesh screen. The extragranular magnesium stearate was added to the V-blender and blended for 2 minutes at 25 RPM. The dry mix was discharged from the V-blender.

5. Compression

[00162] A 24 station Fettle tablet press was equipped with eight 0.724'' x 0.7480'' modified oval, concave, type B flat face machining elements. The dry mixture was added to the funnel of the tablet press. Using a tablet press tower speed of 15 to 25 RPM, the dry blend was compressed into tablets with a target weight of 950 to 1050 mg and a hardness of 9 to 15 kp. In-process checks were performed during compression for appearance, weight, hardness and thickness. The obtained tablets were stored in double coated poly bags with desiccant bags between the bags at 2 to 8°C until coating was carried out.

6. Coating

[00163] Coating solution - 5% total solids concentration with a weight ratio of 3:1 HPMC (Grade - E50 Premium LV): diacetylated monoglycerides, NF Grade-(Myvacet 9-45K). The solution was prepared by dispensing the diacetylated monoglycerides in sterile irrigation water, USP. Then HPMC (E50) was slowly added to the solution, keeping stirring at the same time and stirring continued until a homogeneous suspension was produced.

[00164] Coating was then performed on a Vector-Freund LDCS Hi-Coater device with the following settings: - Inlet temperature: 65°C (Range: 60 to 70°C) - Air flow: 60 CFM (Range: 55 at 65 CFM) - Spray rate: 10 g/min (Range: 6 to 14 g/min) - Atomizing air pressure: 137.8 kPa (Range: 103.4 to 172.3 kPa) [20 psi ( Range: 15 to 25 psi)] - Standard air pressure: 89.6 kPa (Range: 68.9 to 110.3 kPa) [13 psi (Range: 10 to 16 psi)] - Exhaust temperature (result depending on other coater settings): target = 43°C

[00165] The tablets were added to the appropriately sized coating pan and the pan installed in the coater. The spray nozzle was then installed and the standard atomization and air pressures were adjusted. The inlet and exhaust air fans were turned on and the inlet temperature was set to the target value. The pan was then set to a slow stirring speed and circulated while the exhaust temperature was raised to the target value. The inlet air inflow was adjusted to the target flow. Once the exhaust temperature reached the target value, a sample of tablets was retrieved from the coating pan and their weight obtained. The target weight for a weight gain of 5 to 7.5% was calculated based on the sample weight. The sample was placed back in the coating pan and the pan was immediately set to a target speed of 16 RPM (range: 12 to 20 RPM). Immediately, spraying of the coating solution at the target spray rate was started. At different intervals during the coating process, a sample of tablets was taken from the coating pan and the weight was measured. Once the target weight gain of 5 to 7.5% was achieved for a sample (the weight gain for the batches that have been produced to date shown in the following table), the inlet airflow heating was turned off. and the pan returned to the previously used stirring conditions. Once the exhaust temperature reached a value of < or = 30°C, the pan agitation was stopped and the tablets recovered.

Example 2: Large-scale manufactured batches

[00166] The following large-scale batches were manufactured following the procedure described in example 1. Table 1 below summarizes the amounts of excipient used in the manufacture of each of the 6 batches.

[00167] Microcrystalline Cellulose (MCC) is used as a loading/compression aid in the formulation. Two types of MCC were evaluated. One of the manufacturers demonstrated that Prosolv SMCC90, silicified microcrystalline cellulose, has better powder flow than non-silicified MCC.

[00168] KG-1000 is used as an alternative to the SMCC90, another type of MCC. According to one of the manufacturers: KG-1000 has the lowest bulk density among the MCC grades. KG-1000 shows superior packability compared to other standard MCC grades. KG-1000 particles have extremely large L/D value. The particles easily arranged perpendicular to the force applied through compaction; in this way the contact area of the MCC particles is increased. Particle entanglement also occurs easily under a compressive force that provides additional compactability.

[00169] Mg Stearate is used as a lubricant in the formulation.

[00170] Trehalose is used as a binder and drug delivery aid.

[00171] PEO (Polyethylene oxide of different molecular weights) is used as the controlled release, swelling and wearable polymer that imparts gastric retention properties to the tablet.

[00172] HPMC (hydroxypropyl methyl cellulose, hypromellose) is a wearable hydrophilic polymer and is used as a binder in the formulation.

[00173] Myvacet 9-45K is a type of diacetylated monoglyceride and is used as a plasticizer in the formulation coating.

Example 3A: in vitro drug dissolution/release

[00174] Drug release rates for the six large-scale produced formulations were measured using an indirect method, given that colesevelam and colesevelam hydrochloride are insoluble polymers and their concentrations cannot be measured by standard direct HPLC methods used for soluble drugs .

[00175] The drug release rate from the tablets was measured in vitro in acetate buffer pH 4.5 (100 mM) containing 2 mg/mL concentration of a known bile acid (glycocholic acid). Bile acid depletion during swelling and tablet wear was measured and compared with values obtained for a series of standard solutions of known bile acid concentration. The rate of bile acid depletion corresponds to the rate of drug release. These drug release rate results were obtained using a USP Type II apparatus (paddle) with the tablets placed on trays. Results are summarized in figure 1.

Example 3B: In vitro disintegration

[00176] Disintegration media (800 mL pH 4.5, 100 mM acetate buffer) was placed in three disintegration vessels and naturally heated to approximately 37°C. A small drop of the medium was placed on the edge of the disintegration disks. These discs were then compressed into tablets and held together for about 5 to 10 seconds. The tablet and disk were placed in a disintegration tester and testing was started. Three tablets were tested simultaneously in each vessel with visual observation of the disintegration time. Under these conditions, batch 3 disintegrated in about 8.5 to 9 hours. Under these conditions, batch 4 disintegrates in about 9.5 to 10 hours.

Example 3C: in vitro swelling capacity

[00177] Swellability estimates were performed by adhering tablets to glass microscope slides then placing the slides in 1 L beakers. A 900 mL volume of deionized water was then carefully added to each beaker. One beaker was used for each time point and the beakers were placed on an orbital shaker at a temperature of 37°C and 100 RPM. For each time point, a beaker was removed from the shaker and the tablet adhering to the slide was recovered. The tablet with the slide was then placed in a TA.xt plus Texture analyzer (from Texture Technologies Co.) equipped with a cylindrical probe. The probe was lowered to be directly above the tablet. The probe was then lowered further into the swollen layer of the tablet until it reached the swollen core of the tablet. The measurement of force as a function of distance was obtained as the probe penetrated the tablet. The distance from the beginning of the swollen layer to the tablet core represents the thickness of the swollen layer. The measurements obtained on the tablets separated at different times can be plotted to determine the swelling rate of the tablets. See Figure 9 for some data obtained with the formulations (lots 1 to 5) prepared here.

Examples 4: Identification of manufacturing parameters that influence drug release rates

[00178] Certain manufacturing parameters have been identified to play a large role in drug release rate in addition to formulation composition parameters. These included coating level and granulation particle size.

[00179] The impact of coating level on drug release rates for formulations 1 to 5 (coated tablets at levels of approximately 2.5, 4.5 and 7% weight gains compared to uncoated tablets) are summarized in the graphs presented in figures 2 to 6.

Example 5: Alternative protocol for the preparation of formulation 3

[00180] Formulation 3 was resynthesized using an alternative large-scale protocol described below:

1. Intragranular mix

[00181] Intragranular components (except magnesium stearate) were dispensed and passed through a 20 mesh sieve. Components were added to a V-blender and blended for 10 minutes at 25 RPM. Intragranular magnesium stearate was then dispensed and passed through a 20 mesh screen. Magnesium stearate was added to the V-blender and blended for 3 minutes at 25 RPM. The resulting intragranular mixture was discharged from the V-blender.

2. Piece formation

[00182] A 24-station Fettle tablet press was equipped with eight 0.6250'' round bottom, type B flat face machining elements. The intragranular mixture obtained above was added to the funnel of the tablet press. Using a tablet press tower speed of 15 to 25 RPM, the blend was compressed into pieces with a target weight of 1200 to 1400 mg and a hardness of 9 to 15 kP. In-process checks were performed during piece formation regarding appearance, weight, hardness and thickness.

3. Crushing

[00183] A Quadro Comil apparatus equipped with eight of the sieves (2C125G03723390 - 0.125” hole size or 2C109G03727333 - 0.109” hole size) and a straight impeller (square). The pieces obtained previously were transferred to the funnel of the Quadro Comil apparatus. The pieces were ground at 2000 RPM and the ground granulation recovered. The yield for the recovered granulation was calculated.

4. Extragranular mix

[00184] The required amounts of the extragranular components were determined based on the yield of the crushed granulation step. The extragranular components (except magnesium stearate) were then dispensed and passed through a 20 mesh sieve. A portion of the ground granulation was added to a V-blender. The dispensed extragranular components were then added to the V-blender and blended for 10 minutes at 19 RPM. The extragranular magnesium stearate was then dispensed and passed through a 20 mesh screen. The extragranular magnesium stearate was added to the V-blender and blended for 3 minutes at 19 RPM. The dry mix was discharged from the V-blender.

5. Compression

[00185] A 24 station Fettle tablet press was equipped with eight 0.724'' x 0.7480'' modified oval, concave, type B flat face machining elements. The dry mixture was added to the funnel of the tablet press. Using a tablet press tower speed of 15-25 RPM, the dry blend was compressed into tablets with a target weight of chunks with a target weight of 950-1150 mg and a hardness of 12 to 30 kP. In-process checks were performed during compression for appearance, weight, hardness and thickness. The obtained tablets were stored in double coated poly bags with desiccant bags between the bags at 2 to 8°C until coating was carried out.

6. Coating

[00186] Coating solution - 5% total solids concentration with a weight ratio of 3:1 HPMC (Grade - E50 Premium LV): diacetylated monoglycerides, NF Grade (Myvacet 9-45K). The solution was prepared by dispensing the diacetylated monoglycerides in sterile irrigation water, USP. Then HPMC (E50) was slowly added to the solution, keeping stirring at the same time and stirring continued until a homogeneous suspension was produced. Coating was then performed in a Vector-Freund LDCS Hi-Coater with the following settings: - Inlet temperature: 65°C (Range: 60 to 70°C) - Airflow: 60 CFM (Range: 55 to 65 CFM ) - Spray rate: 12 g/min (Range: 6 to 14 g/min) - Atomization air pressure: 137.8 kPa (Range: 103.4 to 172.3 kPa) [20 psi (Range: 15 at 25 psi)] - Standard air pressure: 89.6 kPa (Range: 68.9 to 110.3 kPa) [13 psi (Range: 10 to 16 psi)] - Exhaust temperature (result depending on other settings of the coater): target 45°C

[00187] Tablets were added to the appropriately sized coating pan and the pan installed in the coater. The spray nozzle was then installed and the standard atomization and air pressures were adjusted. The inlet and exhaust air fans were turned on and the inlet temperature was set to the target value. The pan was then set to a slow stirring speed and circulated while the exhaust temperature was raised to the target value. The inlet air inflow was adjusted to the target flow. Once the exhaust temperature reached the target value, a sample of tablets was retrieved from the coating pan and their weight obtained. The amount of target coating solids to be sprayed onto the tablets to achieve a tablet weight gain of at least 3.0% of the coating solids was calculated based on the sample weight. The sample was placed back in the coating pan and the pan was immediately set to a target speed of 16 RPM (range: 12 to 20 RPM). Immediately, spraying of the coating solution at the target spray rate was started. At different intervals during the coating process, a sample of tablets was taken from the coating pan and the weight was measured. Since the target weight gain based on solids was at least 3.0% for one sample, the inlet airflow temperature was reduced to 50°C (range: 45 to 55°C). The pan speed was reduced to 3 RPM (range: 2 to 4 RPM) and the tablets were dried for 10 minutes in run mode. The heating was then turned off and the pan returned to the previously used running conditions. Once the exhaust temperature reached a value of < or = 30°C, the pan run was stopped and the tablets recovered.

Example 6: Study of dog image formation

[00188] Beagle dogs were selected for use in this study based on anatomical, physiological, and biochemical similarities with humans, which facilitates extrapolation of properties observed in humans. The dog's stomach pylorus is much smaller than that of a human, so these preclinical imaging data in dogs provides an in vivo estimate of formulation wear time, but does not provide an absolute gastric retention time in humans. . However, comparison with an immediate release formulation suggests that the tested formulations remain in the animal's stomach for extended periods of time.

[00189] In this study, dogs were administered as a single tablet containing colesevelam hydrochloride formulated as a gastric retention formulation and containing barium sulfate strips in the shape of an “X”. After administration, the stomach was imaged using fluoroscopy and digital X-rays. Various formulations were tested in each dog such that each formulation was administered once followed by at least a 2 day washout period to administer the next formulation until all animals were administered each formulation. Fluoroscopic images of the stomach and intestinal tract were taken at certain time points after dose administration until separation of the radiopaque “X” in the tablet was noted.

[00190] Four different formulations were analyzed in this study. A slow release formulation that corresponds to formulation 4 (or lot 4) in the protocols and figures above; an intermediate release formulation that corresponds to formulation 3 (or lot 3) in the previous protocols and figures; a rapid-release formulation, which was obtained by the procedure described above, and an immediate-release formulation, also prepared by the protocol described below. This study showed that the amount of time after oral administration required for various formulations to dissolve/wear off in the canine stomach was approximately the same for all formulations tested, despite different in vitro release profiles. Most importantly, however, he showed that the immediate release formulation had the fastest average erosion rate at around 45 min, being completely eroded in the dog at least 5 hours faster than any of the other formulations tested (these data are summarized in Figure 7 and Figure 8).

Preparation of the quick release formulation

[00191] Intragranular components (Colesevam HCl and Microcrystalline Cellulose - KG1000), were weighed and passed through a 20 mesh sieve then added to a V-blender. The mixture was mixed for 10 minutes. Magnesium stearate was then passed through a 20 mesh sieve, weighed and adhered to the mixture contained in the V-blender. The mixture was combined for a further 2 minutes. A rotary tablet press was fitted with a 0.6250” round stainless steel straight tool. The mixture was added to the funnel. Chunks were prepared at a target weight of 1350 mg and a hardness of 11 to 12 kP. The pieces were ground with the Quadro Comill (sieve size 7L 109G03127* 2769, impeller speed = 2000 rpm) and the resulting dry granules were collected. The yield after granulation was determined. The dried granules were added to the V-blender. Extragranular excipients (polyethylene oxide and microcrystalline cellulose - KG1000) were passed through a 20 mesh sieve, added to a V-blender and mixed for 10 minutes. Magnesium stearate was then passed through a #20 mesh sieve, weighed and added to the mixture. The mixture was mixed for a further 2 minutes. The tablet press was fitted with a modified 0.4724” x 0.7480” oval tool. Tablets were produced at a target weight of 1015-1025 mg and target hardness of 14-15 kp.

[00192] The tablets were coated to a weight gain of 6.2% in a pan coater using a solids concentration of 5% with diacetylated monoglycerides (Myvacet 9-45K) and hydroxypropylmethyl cellulose (Methocel E50) and the following conditions process temperature: Inlet temperature: 60°C Exhaust temperature: 42 to 43°C Air flow: 40 CFM Solution rate: 4.0 g/m Atomizing air: 150 kPa (1.5 bar) Standard air: 100 kPa (1.0 bar) Drum speed: 16 rpm Immediate release formulation preparation: Composition: Core tablet: 74 / 25 / 1 Colesevelam HCl / Silicified Microcrystalline Cellulose - Grade: SMCC90) / Magnesium Stearate Coating: Core tablets are coated at an 8 to 9% weight gain. Coating composition: 75 / 25 Hydroxypropylmethyl Cellulose (Methocel E50) / Diacetylated Monoglycerides (Myvacet 9-45K)

Preparation:

[00193] Colesevelam HCl and microcrystalline cellulose - SMCC90 were weighed and passed through a 20 mesh sieve then added to a V-blender. The mixture was blended for 10 minutes. Magnesium stearate was then passed through a 20 mesh sieve, weighed and added to the mixture contained in the V-blender. The mixture was combined for a further 2 minutes. A rotary tablet press was fitted with a modified 0.4724” x 0.7480” oval tool. Tablets were produced at a target weight of approximately 850 mg and target hardness of 17 kp.

[00194] The tablets were coated to a weight gain of 8.7% in a pan coater using a solids concentration of 5% with diacetylated monoglycerides (Myvacet 9-45K) and hydroxypropylmethyl cellulose (Methocel E50) and the following conditions process: Inlet temperature: 60°C; Exhaust temperature: 42 to 43°C Air flow: 40 CFM Solution rate: 4.0 g/m Atomizing air: 150 kPa (1.5 bar) Standard air: 100 kPa (1.0 bar) drum: 16 rpm.

Claims (19)

1. Oral gastric retention dosage form in the form of a tablet, characterized in that it comprises a bile acid sequestrant selected from colesevelam and colesevelam hydrochloride, dispersed in a polymeric matrix comprising one or more hydrophilic polymers, wherein at least a hydrophilic polymer is a poly(alkylene) oxide, for prolonged release of a bile acid sequestrant to the stomach for the treatment of a disease of the upper gastrointestinal tract or throat. 2. Oral gastric retention dosage form according to claim 1, characterized in that, upon inhibition of gastric fluid, said dosage form swells to a size sufficient to promote gastric retention for a period of time of 3 hours or more and that the bile acid sequestrant is released from the dosage form through erosion of the polymer matrix for an extended period of time of at least 3 hours. 3. Oral gastric retention dosage form according to claim 1 or 2, characterized in that the polymer matrix degrades during a drug release period, wherein the drug release period is at least 6 hours . 4. Oral gastric retention dosage form according to any of the preceding claims, characterized in that the drug release rate is measured IN VITRO, in acetate buffer at pH 4.5, using a USP type II device ( paddles) with the tablets placed in bins is such that no more than 40% percent of the drug has been released from the dosage form after 4 hours. 5. Oral gastric retention dosage form according to any one of the preceding claims, characterized in that the drug release rate is measured IN VITRO, in acetate buffer at pH 4.5, using a USP type II device ( paddles) with the tablets placed in bins is such that between 75 and 100% percent of the drug has been released from the dosage form after 16 hours. 6. Oral gastric retention dosage form, according to claim 1, characterized in that the hydrophilic polymer matrix comprises two hydrophilic polymers. 7. Oral gastric retention dosage form according to any one of claims 1 to 6, characterized in that the poly(alkylene) oxide is present in an amount ranging from a proportion of 40 percent by weight to a proportion of 75 percent by weight. 8. A gastric retention oral dosage form according to any one of claims 1 to 7, characterized in that the poly(alkylene) oxide is present in an amount ranging from a proportion of 40 percent by weight to a proportion of 50 percent by weight. A gastric retention oral dosage form according to any one of claims 1 to 8, characterized in that a second hydrophilic polymer of the one or more hydrophilic polymers is used as a binder and is selected from povidone, starch, hydroxypropyl cellulose and hydroxypropylmethylcellulose. 10. Oral gastric retention dosage form according to any one of claims 1 to 9, characterized in that the dose of the bile acid sequestrant is between 400 mg and 750 mg. 11. Oral gastric retention dosage form according to any one of the preceding claims, characterized in that the dose of the bile acid sequestrant is between 400 mg and 600 mg. 12. Oral gastric retention dosage form according to any one of the preceding claims, characterized in that it additionally comprises a coating, wherein the coating level is between 5% and 7.5% (weight: weight) by weight tablet total. A gastric retention oral dosage form according to any one of claims 1 to 12, characterized in that it additionally comprises a coating, wherein the coating comprises a microcrystalline cellulose and an acetylated glyceride. A gastric retention oral dosage form according to any preceding claim, characterized in that said gastric retention oral dosage form swells to a size that is at least 130% of the original size within 2 hours. 15. A gastric retention oral dosage form according to any one of claims 1 to 14, characterized in that said gastric retention oral dosage form comprises two polymers, wherein both polymers are a hydrophilic and intumescent degradable polymer. . 16. A gastric retention oral dosage form according to any one of claims 1 to 14, characterized in that said gastric retention oral dosage form comprises two polymers, one of the polymers being a hydrophilic and intumescent degradable polymer. and the other polymer is a non-degradable, non-hydrophilic, intumescent polymer. 17. A gastric retention oral dosage form according to any one of claims 1 to 14, characterized in that said gastric retention oral dosage form comprises two polymers, one of the polymers being a hydrophilic and intumescent degradable polymer. and the other is a non-swelling, hydrophilic, degradable polymer. 18. Use of a total daily dose of from about 1500 mg to about 3000 mg of a bile acid sequestrant in the gastric retention oral dosage form as defined in any one of claims 1-17, characterized in that it is for manufacture of a medicament for the treatment of a subject suffering from a disease selected from heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, esophageal ulcers, esophagitis, laryngitis, pharyngitis, deep voice, gastroesophageal reflux disease (GERD), Barrett's esophagus, gastric cancer, cancer of the esophagus (eg, adenocarcinoma), gastritis, and GERD-related lung dysfunction. 19. Use of a total daily dose of about 100 mg to about 4,000 mg of a bile acid sequestrant in the gastric retention oral dosage form as defined in claim 1, characterized in that it is for the manufacture of a medicament for the treatment of an individual suffering from a disease selected from heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, esophageal ulcers, esophagitis, laryngitis, pharyngitis, deep voice, gastroesophageal reflux disease (GERD), the Barrett's esophagus, gastric cancer, cancer of the esophagus (eg, adenocarcinoma), gastritis, and GERD-related lung dysfunction.

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